Treatment of pulmonary hypertension with carbonic anhydrase inhibitors

ABSTRACT

This disclosure relates generally to methods and pharmaceutical compositions useful in treating pulmonary hypertension. In one embodiment, for example, the disclosure provides a method for treating pulmonary hypertension comprising administering a therapeutically effective dose of a carbonic anhydrase inhibitor to a patient in need of treatment. The disclosure finds utility in the fields of medicine and pharmacology.

TECHNICAL FIELD

This disclosure relates generally to methods and pharmaceuticalcompositions useful in treating pulmonary hypertension. The disclosurefinds utility in the fields of medicine and pharmacology.

BACKGROUND

Pulmonary hypertension (PH), also known as pulmonary arterialhypertension (PAH), is a disorder characterized by high blood pressurein the arteries that supply the lungs. Pulmonary hypertension is oftenclassified as either secondary pulmonary hypertension (SPH), in whichthe cause of the elevated blood pressure is known, or primary pulmonaryhypertension (PPH), in which the cause is unknown. Examples ofpre-existing conditions that may cause SPH include chronic obstructivepulmonary disease (COPD), sleep apnea, emphysema, bronchitis,sclerodema, CREST syndrome, systemic lupus erythematosus, chronicpulmonary thromboembolism, HIV infection, liver disease, and certaincongenital heart diseases. Certain diet drugs such as fenfluramine anddexfenfluramine may also cause SPH.

In addition to high arterial blood pressure, PH may also becharacterized by: narrowing and/or stiffening of the pulmonary arteriesas the muscles within the walls of the arteries tighten or thicken; theformation of scar tissue in the walls of the pulmonary arteries; and theformation of blood clots within the smaller pulmonary arteries.

Symptoms of pulmonary hypertension include shortness of breath withminimal exertion, fatigue, chest pain, dizzy spells, low blood pressure,and fainting. The blood pressure in the pulmonary arteries of a patientsuffering from PH may be twice as high or higher than the pulmonaryblood pressure in a normal, healthy individual.

Although PPH is extremely rare, occurring in about two persons permillion population per year, SPH is far more common and represents asignificant medical concern for the population as a whole. Pulmonaryhypertension is frequently misdiagnosed and progresses to late stagebefore it is accurately diagnosed.

There is no known cure for PH; current methods of treatment focus onprolonging patient lifespan and enhancing patient quality of life.Current methods of treatment of PH include administration of:vasodilators such as prostacyclin, epoprostenol, and sildenafil;endothelin receptor antagonists such as bosentan; calcium channelblockers such as amlodipine, diltiazem, and nifedipine; anticoagulantssuch as warfarin; and diuretics. Treatment of PH has also been carriedout using oxygen therapy; and lung and/or heart transplantation. Each ofthese methods, however, suffers from one or multiple drawbacks which mayinclude lack of effectiveness, serious side effects, low patientcompliance, and high cost.

An ideal method of treatment would eliminate or significantly reduce thesymptoms of PH, would lower pulmonary pressures, would be substantiallymore effective and easy to administer, and would have minimal or no sideeffects. The present disclosure is directed at providing one or more ofthese characteristics in a chemotherapeutic method for treating PH.

SUMMARY OF THE DISCLOSURE

The present disclosure describes compositions and methods for treatingpulmonary hypertension.

In one embodiment, then, the present disclosure describes a method fortreating pulmonary hypertension in a patient. The method comprisesadministering a therapeutically effective dose of a carbonic anhydraseinhibitor to the patient.

In another embodiment, the present disclosure describes a method fortreating pulmonary hypertension in a patient. The method comprisesadministering to the subject a daily dose of a carbonic anhydraseinhibitor that is gradually increased, over an extended time period,from an initial daily dosage up to a final daily dosage suitable forcontinued maintenance therapy. The final daily dosage is in the range ofabout 10 mg to 400 mg.

In another embodiment, the present disclosure describes a pharmaceuticalformulation comprising a therapeutically effective amount of a carbonicanhydrase inhibitor. The pharmaceutical formulation further comprises atleast one additional active agent selected from a Type Vphosphodiesterase inhibitor and an endothelin antagonist.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Nomenclature

Before describing the present invention in detail, it is to beunderstood that unless otherwise indicated, this invention is notlimited to particular formulations, active and inactive agents, modes ofadministration, or methods of treatment or use, as such may vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example, “anactive agent” refers not only to a single active agent but also to acombination of two or more different active agents, “a dosage form”refers to a combination of dosage forms as well as to a single dosageform, and the like. Unless defined otherwise, all technical andscientific terms used herein have the meaning commonly understood by oneof ordinary skill in the art to which the invention pertains. Althoughany methods and materials similar or equivalent to those describedherein may be useful in the practice or testing of the presentinvention, preferred methods and materials are described below. Specificterminology of particular importance to the description of the presentinvention is defined below.

When referring to an active agent, applicants intend the term “activeagent” to encompass not only the specified molecular entity but also itspharmaceutically acceptable, pharmacologically active analogs,including, but not limited to, salts, esters, amides, prodrugs,conjugates, active metabolites, and other such derivatives, analogs, andrelated compounds.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. Thus,“treating” a patient as described herein encompasses prevention ofpulmonary hypertension in a susceptible individual as well as treatmentof a clinically symptomatic individual by inhibiting or causingregression of disease.

By the terms “effective amount” and “therapeutically effective amount”of a compound of the invention is meant a nontoxic but sufficient amountof the drug or agent to provide the desired effect.

The term “dosage form” denotes any form of a pharmaceutical compositionthat contains an amount of active agent sufficient to achieve atherapeutic effect with a single administration. When the formulation isa tablet or capsule, the dosage form is usually one such tablet orcapsule. The frequency of administration that will provide the mosteffective results in an efficient manner without overdosing will varywith the characteristics of the particular active agent, including bothits pharmacological characteristics and its physical characteristics,such as hydrophilicity.

The term “controlled release” refers to a drug-containing formulation orfraction thereof in which release of the drug is not immediate, i.e.,with a “controlled release” formulation, administration does not resultin immediate release of the drug into an absorption pool. The term isused interchangeably with “nonimmediate release” as defined inRemington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton,Pa.: Mack Publishing Company, 1995). In general, the term “controlledrelease” as used herein includes sustained release and delayed releaseformulations.

The term “sustained release” (synonymous with “extended release”) isused in its conventional sense to refer to a drug formulation thatprovides for gradual release of a drug over an extended period of time,and that preferably, although not necessarily, results in substantiallyconstant blood levels of a drug over an extended time period. The term“delayed release” is also used in its conventional sense, to refer to adrug formulation which, following administration to a patient, providesa measurable time delay before drug is released from the formulationinto the patient's body.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” derivative or analog, refers to a derivativeor analog having the same type of pharmacological activity as the parentcompound and approximately equivalent in degree.

Active Agents, Dosages, and Formulations

The invention involves administration of a carbonic anhydrase inhibitorto a patient afflicted with pulmonary hypertension, generally secondarypulmonary hypertension. Carbonic anhydrase inhibitors are generallyimidazoles (such as imidazole per se), imidazole derivatives,sulfonamides (such as topiramate), and sulfonylureas (such aszonisamide). Any carbonic anhydrase inhibitor may be advantageouslyemployed in conjunction with the present invention. Examples of suitablecarbonic anhydrase inhibitors include, without limitation, acetazolamide(Diamox™), brinzolamide, diclofenamide, dichlorphenamide (Daranide™),dorzolamide, furosemide, imidazole, methazolamide (Neptazane™),phenylalanine, topiramate, and zonisamide. Carbonic anhydrase inhibitorsalso include selective inhibitors of the cyclooxygenase-2 enzyme (“cox 2inhibitors”), such as such as celecoxib, valdecoxib, rofecoxib,etoricoxib, and the like. Preferred carbonic anhydrase inhibitors foruse in conjunction with the present invention include, withoutlimitation, acetazolamide, brinzolamide, diclofenamide,dichlorphenamide, dorzolamide, furosemide, imidazole, methazolamide,phenylalanine, topiramate, zonisamide, celecoxib, valdecoxib, rofecoxib,and etoricoxib, with acetazolamide, zonisamide, and topiramateparticularly preferred. The oral daily dose of topiramate effective totreat pulmonary hypertension according to the method of the invention isgenerally in the range of about 10 mg to about 400 mg, preferably in therange of about 50 mg to about 250 mg, and optimally in the range ofabout 75 mg to about 225 mg. The daily dose may be undivided, such thatcarbonic anhydrase inhibitor is administered once a day, or the dailydose may be divided into two to four individual doses. Preferably, thetopiramate is administered in sustained release form, as will bediscussed infra, either once or twice daily to achieve a daily dosage inthe aforementioned ranges. It will be appreciated that the daily dose oftopiramate as well as other carbonic anhydrase inhibitors normallyrepresents on the order of 25% to 200%, more generally 25% to 100%, andmost typically 25% to 75%, of the daily dose known and/or prescribed forpreviously known indication(s) (as set forth, for example, in thePhysicians' Desk Reference), using the same mode of administration.

In a preferred embodiment, the dosage of the carbonic anhydraseinhibitor is increased gradually at the outset of therapy, generallyover a period of about three to ten weeks, more usually over a period ofabout three to about eight weeks, starting with a relatively low initialdose (on the order of 10 mg to 40 mg topiramate, preferably 15 mg to 35mg topiramate, for instance), in order to reduce the likelihood ofundesirable side effects. With topiramate, for example, a representativedosage regimen is as follows: administration of about 25 mg daily forabout the first 5-7 days of treatment; administration of about 50 mgdaily for the next 5-7 days; administration of about 75 mg daily forabout the next 5-7 days; administration of about 100 mg daily for thenext 5-7 days; and, subsequently, ongoing administration of a dailymaintenance dose in the ranges specified earlier herein.

Administration of the active agent may be carried out using anyappropriate mode of administration. Thus, administration can be, forexample, oral, parenteral, transdermal, transmucosal (including rectal,vaginal, and transurethral), sublingual, by inhalation, or via animplanted reservoir in a dosage form. The term “parenteral” as usedherein is intended to include subcutaneous, intravenous, andintramuscular injection.

Depending on the intended mode of administration, the pharmaceuticalformulation may be a solid, semi-solid or liquid, such as, for example,a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, asuppository, granules, pellets, beads, a powder, or the like, preferablyin unit dosage form suitable for single administration of a precisedosage. Suitable pharmaceutical compositions and dosage forms may beprepared using conventional methods known to those in the field ofpharmaceutical formulation and described in the pertinent texts andliterature, e.g., in Remington: The Science and Practice of Pharmacy(Easton, Pa.: Mack Publishing Co., 1995). For those compounds that areorally active, oral dosage forms are generally preferred, and includetablets, capsules, caplets, solutions, suspensions and syrups, and mayalso comprise a plurality of granules, beads, powders, or pellets thatmay or may not be encapsulated. Preferred oral dosage forms are tabletsand capsules.

As noted above, it is especially advantageous to formulate compositionsof the invention in unit dosage form for ease of administration anduniformity of dosage. The term “unit dosage forms” as used herein refersto physically discrete units suited as unitary dosages for theindividuals to be treated. That is, the compositions are formulated intodiscrete dosage units each containing a predetermined, “unit dosage”quantity of an active agent calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. The specifications of unit dosage forms of the invention aredependent on the unique characteristics of the active agent to bedelivered. Dosages can further be determined by reference to the usualdose and manner of administration of the ingredients. It should be notedthat, in some cases, two or more individual dosage units in combinationprovide a therapeutically effective amount of the active agent, e.g.,two tablets or capsules taken together may provide a therapeuticallyeffective dosage of the carbonic anhydrase inhibitor, such that the unitdosage in each tablet or capsule is approximately 50% of thetherapeutically effective amount.

Tablets may be manufactured using standard tablet processing proceduresand equipment. Direct compression and granulation techniques arepreferred. In addition to the active agent, tablets will generallycontain inactive, pharmaceutically acceptable carrier materials such asbinders, lubricants, disintegrants, fillers, stabilizers, surfactants,coloring agents, and the like.

Capsules are also preferred oral dosage forms for those carbonicanhydrase inhibitors that are orally active, in which case the activeagent-containing composition may be encapsulated in the form of a liquidor solid (including particulates such as granules, beads, powders orpellets). Suitable capsules may be either hard or soft, and aregenerally made of gelatin, starch, or a cellulosic material, withgelatin capsules preferred. Two-piece hard gelatin capsules arepreferably sealed, such as with gelatin bands or the like. See, forexample, Remington: The Science and Practice of Pharmacy, cited earlierherein, which describes materials and methods for preparing encapsulatedpharmaceuticals.

Oral dosage forms, whether tablets, capsules, caplets, or particulates,may, if desired, be formulated so as to provide for controlled releaseof the carbonic anhydrase inhibitor, and in a preferred embodiment, thepresent formulations are controlled release oral dosage forms.Generally, the dosage forms provide for sustained release, i.e.,gradual, release of the carbonic anhydrase inhibitor from the dosageform to the patient's body over an extended time period, typicallyproviding for a substantially constant blood level of the agent over atime period in the range of about 4 to about 12 hours, typically in therange of about 6 to about 10 hours. In a particularly preferredembodiment, there is a very gradual increase in blood level of the drugfollowing oral administration of the dosage form containing the carbonicanhydrase inhibitor, such that peak blood level (generally about 50-200μg/ml for topiramate, about 1-5 μg/ml for zonisamide, or about 10-35μg/ml for acetazolamide), is not reached until at least 4-6 hours haveelapsed, with the rate of increase of blood level drug approximatelylinear. In addition, in the preferred embodiment, there is an equallygradual decrease in blood level at the end of the sustained releaseperiod.

Generally, as will be appreciated by those of ordinary skill in the art,sustained release dosage forms are formulated by dispersing the activeagent within a matrix of a gradually hydrolyzable material such as ahydrophilic polymer, or by coating a solid, drug-containing dosage formwith such a material. Hydrophilic polymers useful for providing asustained release coating or matrix include, by way of example:cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethylcellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylicacid polymers and copolymers, preferably formed from acrylic acid,methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkylesters, and the like, e.g. copolymers of acrylic acid, methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethylmethacrylate; and vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, and ethylene-vinyl acetate copolymer.

Preferred sustained release dosage forms herein are composed of theacrylate and methacrylate copolymers available under the tradename“Eudragit” from Rohm Pharma (Germany). The Eudragit series E, L, S, RL,RS, and NE copolymers are available as solubilized in organic solvent,in an aqueous dispersion, or as a dry powder. Preferred acrylatepolymers are copolymers of methacrylic acid and methyl methacrylate,such as the Eudragit L and Eudragit S series polymers. Particularlypreferred such copolymers are Eudragit L-30D-55 and Eudragit L-100-55(the latter copolymer is a spray-dried form of Eudragit L-30D-55 thatcan be reconstituted with water). The molecular weight of the EudragitL-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da,with a ratio of free carboxyl groups to ester groups of approximately1:1. The copolymer is generally insoluble in aqueous fluids having a pHbelow 5.5. Another particularly suitable methacrylic acid-methylmethacrylate copolymer is Eudragit S-100, which differs from EudragitL-30D-55 in that the ratio of free carboxyl groups to ester groups isapproximately 1:2. Eudragit S-100 is insoluble at pH below 5.5, butunlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having apH in the range of 5.5 to 7.0. This copolymer is soluble at pH 7.0 andabove. Eudragit L-100 may also be used, which has a pH-dependentsolubility profile between that of Eudragit L-30D-55 and Eudragit S-100,insofar as it is insoluble at a pH below 6.0. It will be appreciated bythose skilled in the art that Eudragit L-30D-55, L-100-55, L-100, andS-100 can be replaced with other acceptable polymers having similarpH-dependent solubility characteristics. Other preferred Eudragitpolymers are cationic, such as the Eudragit E, RS, and RL seriespolymers. Eudragit E100 and E PO are cationic copolymers ofdimethylaminoethyl methacrylate and neutral methacrylates (e.g., methylmethacrylate), while Eudragit RS and Eudragit RL polymers are analogouspolymers, composed of neutral methacrylic acid esters and a smallproportion of trimethylammonioethyl methacrylate.

A particularly preferred dosage form according to the invention containsin the range of about 10 mg to about 400 mg topiramate, preferably inthe range of about 50 to about 250 mg topiramate, most preferably in therange of about 75 mg to about 225 mg topiramate, and is formulated usingEudragit RS, Eudragit RL, or a blend of Eudragit RS and Eudragit RL, toprovide sustained release over a time period in the range of about 4 toabout 12 hours, typically in the range of about 6 to about 10 hours,following oral administration of the dosage form to a patient. Suchformulations can be made using conventional means known to those ofordinary skill in the art, for example by coating active agent particleswith the sustained release polymer(s) and either loading the coatedparticles into a capsule or compressing the coated particles into atablet using tabletting excipients and a tablet press.

Preparations according to this invention for parenteral administrationinclude sterile aqueous and nonaqueous solutions, suspensions, andemulsions. Injectable aqueous solutions contain the active agent inwater-soluble form. Examples of nonaqueous solvents or vehicles includefatty oils, such as olive oil and corn oil, synthetic fatty acid esters,such as ethyl oleate or triglycerides, low molecular weight alcoholssuch as propylene glycol, synthetic hydrophilic polymers such aspolyethylene glycol, liposomes, and the like. Parenteral formulationsmay also contain adjuvants such as solubilizers, preservatives, wettingagents, emulsifiers, dispersants, and stabilizers, and aqueoussuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, anddextran. Injectable formulations are rendered sterile by incorporationof a sterilizing agent, filtration through a bacteria-retaining filter,irradiation, or heat. They can also be manufactured using a sterileinjectable medium. The active agent may also be in dried, e.g.,lyophilized, form that may be rehydrated with a suitable vehicleimmediately prior to administration via injection.

The active agent may also be administered through the skin usingconventional transdermal drug delivery systems, wherein the active agentis contained within a laminated structure that serves as a drug deliverydevice to be affixed to the skin. In such a structure, the drugcomposition is contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated structure may contain a single reservoir,or it may contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Alternatively, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir which, in this case, may be either apolymeric matrix as described above, or it may be a liquid or hydrogelreservoir, or may take some other form. Transdermal drug deliverysystems may in addition contain a skin permeation enhancer.

In addition to the formulations described previously, the active agentmay be formulated as a depot preparation for controlled release of theactive agent, preferably sustained release over an extended time period.These sustained release dosage forms are generally administered byimplantation (e.g., subcutaneously or intramuscularly or byintramuscular injection).

Although the present compositions will generally be administered orally,parenterally, transdermally, or via an implanted depot, other modes ofadministration are suitable as well. For example, administration may betransmucosal, e.g., rectal or vaginal, preferably using a suppositorythat contains, in addition to the active agent, excipients such as asuppository wax. Transmucosal administration also encompassestransurethral administration, as described, for example, in U.S. Pat.Nos. 5,242,391, 5,474,535, and 5,773,020 to Place et al. Formulationsfor nasal or sublingual administration are also prepared with standardexcipients well known in the art. The pharmaceutical compositions of theinvention may also be formulated for inhalation, e.g., as a solution insaline, as a dry powder, or as an aerosol.

In another embodiment of the invention, the method of treating thepatient involves administering at least one additional active agent,i.e., in addition to the carbonic anhydrase inhibitor. The additionalactive-agent may be, for example, a sympathomimetic amine, a Type Vphosphodiesterase inhibitor, and/or an endothelin antagonist. In somecases, the additional active agent will reduce the quantity of thecarbonic anhydrase inhibitor needed to achieve a therapeutic effect,e.g., a sympathomimetic amine such as phentermine or bupropion canreduce the minimum effective amount of a carbonic anhydrase inhibitorsuch as topiramate, zonisamide, or acetazolamide.

Sympathomimetic amines, including the catecholamines, are amine drugsthat mimic the actions of drugs that activate the sympathetic nervoussystem, such as epinephrine and norepinephrine. Sympathomimetic aminesthus include amphetamine, benzphetamine, bupropion, chlorphentermine,colterol, diethylpropion, dopamine, dobutamine, ephedrine, epinephrine,epinine, ethylnorepinephrine, fenfluramine, fenoldapam,hydroxyamphetamine, ibopamine, isoetharine, isoproterenol,mephentermine, metaproterenol, metaraminol, methoxamine,methoxyphenamine, midodrine, norepinephrine, phendimetrazine,phenmetrazine, phentermine, phenylephrine, phenylethylamine,phenylpropanolamine, prenalterol, propylhexedrine, protokylol,ritodrine, terbutaline, tuaminoheptane, tyramine, and acid additionsalts thereof, either organic or inorganic. Common acid addition saltsof some of the aforementioned sympathomimetic amines include, withoutlimitation, dobutamine hydrochloride, epinephrine bitartrate,ethylnorepinephrine hydrochloride, fenoldopam mesylate,hydroxyamphetamine hydrobromide, isoproterenol hydrochloride,mephentermine sulfate, metaraminol bitartrate, methoxaminehydrochloride, norepinephrine bitartrate, phenylephrine hydrochloride,and terbutaline sulfate.

Preferably, the sympathomimetic amine is phentermine, chlorphentermine,or bupropion, with phentermine and bupropion particularly preferred. Inan exemplary embodiment, the carbonic anhydrase inhibitor administeredis topiramate and the sympathomimetic amine administered is phentermine,wherein the daily dose of topiramate is as given above for themonotherapeutic regimen, and the corresponding daily dose of phenterminethat is co-administered is such that the weight ratio of the daily doseof topiramate to the daily dose of phentermine is in the range of about2.5:1 to about 20:1, typically in the range of about 5:1 to about 20:1.In another exemplary embodiment, the carbonic anhydrase inhibitoradministered is topiramate and the sympathomimetic amine administered isbupropion, wherein the daily dose of topiramate is as given above forthe monotherapeutic regimen, and the corresponding daily dose ofbupropion that is co-administered is such that the weight ratio of thedaily dose of topiramate to the daily dose of bupropion is in the rangeof about 1:5 to about 3:1, preferably in the range of about 1:4 to about2:1, most preferably in the range of about 1:4 to about 1.5:1

When the method of the invention involves combination therapy, i.e.,wherein a secondary agent such as a sympathomimetic amine isco-administered with a carbonic anhydrase inhibitor, the agents may beadministered separately, at the same or at different times of the day,or they may be administered in a single composition. In the former case,it is generally preferred that the sympathomimetic amine be administeredlater in the day than the carbonic anhydrase inhibitor, particularlywhen the amine drug acts as a CNS stimulant and could interfere withsleep. In the latter case, each agent can be administered in an“immediate release” manner or in a “controlled release manner.” When theadditional active agent is a sympathomimetic amine, for instance, anydosage form containing both active agents, i.e., both the carbonicanhydrase inhibitor and the sympathomimetic amine, can provide forimmediate release or controlled release of the sympathomimetic amine,and either immediate release or controlled release of the carbonicanhydrase inhibitor. It is preferred, however, that the carbonicanhydrase inhibitor be in controlled release form, as described suprawith respect to carbonic anhydrase inhibitor monotherapy. As an example,a combination dosage form of the invention for once-daily administrationmight contain in the range of about 50 mg to about 400 mg topiramate,preferably about 50 mg to about 250 mg topiramate, and optimally about50 mg to about 150 mg topiramate, in controlled release (e.g., sustainedrelease) form, and either phentermine in immediate release form, orbupropion in controlled release form, with the additional active agentpresent in an amount that provides a weight ratio of topiramate tophentermine, or a weight ratio of topiramate to bupropion, specified asabove. In other formulations of the invention, two or more additionalactive agents, which may or may not be in the same class of drug (e.g.,sympathomimetic amines), can be present in combination, along with thecarbonic anhydrase inhibitor. In such a case, the effective amount ofeither or each individual additional active agent present will generallybe reduced relative to the amount that would be required if only asingle added agent were used. Specific examples of such once-dailyformulations include the following:

(1) 200 mg topiramate, 15 mg phentermine;

(2) 200 mg topiramate, 10 mg phentermine;

(3) 150 mg topiramate, 15 mg phentermine;

(4) 150 mg topiramate, 10 mg phentermine;

(5) 100 mg topiramate, 15 mg phentermine;

(6) 100 mg topiramate, 10 mg phentermine;

(7) 200 mg topiramate, 300 mg bupropion;

(8) 200 mg topiramate, 250 mg bupropion;

(9) 200 mg topiramate, 200 mg bupropion;

(10) 200 mg topiramate, 150 mg bupropion;

(11) 200 mg topiramate, 100 mg bupropion;

(12) 100 mg topiramate, 300 mg bupropion;

(13) 100 mg topiramate, 250 mg bupropion;

(14) 100 mg topiramate, 200 mg bupropion;

(15) 100 mg topiramate, 150 mg bupropion;

(16) 100 mg topiramate, 100 mg bupropion;

(17) 200 mg topiramate, 300 mg bupropion, 5 mg phentermine;

(18) 150 mg topiramate, 300 mg bupropion, 5 mg phentermine;

(19) 100 mg topiramate, 300 mg bupropion, 5 mg phentermine;

(20) 200 mg topiramate, 250 mg bupropion, 10 mg phentermine;

(21) 150 mg topiramate, 250 mg bupropion, 10 mg phentermine; and

(22) 100 mg topiramate, 250 mg bupropion, 10 mg phentermine.

As may be deduced from the foregoing, representativetopiramate/phentermine formulations typically contain 100 mg to 200 mgtopiramate and: 100 mg to 300 mg bupropion; 10 mg to 15 mg phentermine;or 100 mg to 300 mg bupropion and 5 mg to 10 mg phentermine. Theadditional active agent may also be a Type V phosphodiesteraseinhibitor, administered with the carbonic anhydrase inhibitor, or withboth the carbonic anhydrase inhibitor and a sympathomimetic amine.Examples of Type V phosphodiesterase inhibitors include, withoutlimitation, avanafil, sildenafil, tadalafil, zaprinast, dipyridamole,vardenafil and acid addition salts thereof. Avanafil, described in U.S.Pat. No. 6,656,935, is particularly preferred. In an exemplaryembodiment, the carbonic anhydrase inhibitor administered is topiramateand the Type V phosphodiesterase inhibitor administered is avanafil,tadalafil, or sildenafil, wherein the daily dose of topiramate is asgiven above for the monotherapeutic regimen, and the corresponding dailydose of avanafil that is co-administered is such that the weight ratioof topiramate to avanafil is in the range of about 3:1 to about 1:3,typically in the range of about 2:1 to about 1:2. For sildenafil, whichis approximately twice as potent as avanafil, the corresponding dailydose co-administered with topiramate is in the range of about 6:1 toabout 1:1.5, typically about 4:1 to about 1:1. For tadalafil, which is astill more potent phosphodiesterase inhibitor, the daily dose whenco-administered in combination with topiramate according to the methodof the invention is in the range of about 36:1 to about 4:1, typicallyin the range of about 24:1 to about 6:1.

The additional active agent may also be an endothelin receptorantagonist, e.g., bosentan, sitaxsentan, or ambrisentan, with bosentanpreferred.

Combination therapy involving a carbonic anhydrase inhibitor and eitheravanafil or bosentan will generally involve administration of a singledosage form that contains in the range of about 50 mg to about 400 mgtopiramate, optimally about 50 mg to about 150 mg topiramate, insustained release form, and avanafil or bosentan, also preferably insustained release form. When the additional active agent is avanafil,the amount in the dosage form will generally be such that the weightratio of topiramate to avanafil provided will be in the range of about3:1 to about 1:3, preferably about 2:1 to about 1:2, as noted above.With bosentan, the preferred weight ratio of topiramate to bosentan isin the range of about 0.5:1 to about 2:1.

In the method of the invention, the carbonic anhydrase inhibitor isadministered to a person suffering from pulmonary hypertension, eitherprimary pulmonary hypertension or secondary pulmonary hypertension. Thecarbonic anhydrase inhibitor is administered alone or in combinationwith one or more additional active agents, within the context of adosing regiment as described above. It has also been found that thecarbonic anhydrase inhibitor alleviates or otherwise treats certaincauses of pulmonary hypertension, primarily secondary pulmonaryhypertension, such as sleep apnea and chronic obstructive pulmonarydisease. It has additionally been found that administration of acarbonic anhydrase inhibitor according to the present invention improvesthe patient's cardiac index (or cardiac output). Further, it has beenfound that administration of a carbonic anhydrase inhibitor alleviatesor otherwise treats certain adverse physiological conditions in additionto pulmonary hypertension, conditions that are often present in patientsafflicted with pulmonary hypertension, usually, but not necessarily,with secondary pulmonary hypertension. One such condition is congestiveheart failure. Accordingly, the invention further encompasses methods oftreating congestive heart failure, sleep apnea, and chronic obstructivepulmonary disease using a carbonic anhydrase inhibitor, optionally incombination with one or more additional active agents, at doses and informulations as described above.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties. However, where apatent, patent application, or publication containing expressdefinitions is incorporated by reference, those express definitionsshould be understood to apply to the incorporated patent, patentapplication, or publication in which they are found, and not to theremainder of the text of this application, in particular the claims ofthis application.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples that follow, are intendedto illustrate and not limit the scope of the invention. It will beunderstood by those skilled in the art that various changes may be madeand equivalents may be substituted without departing from the scope ofthe invention, and further that other aspects, advantages andmodifications will be apparent to those skilled in the art to which theinvention pertains.

EXAMPLE 1

A 26 year-old female with obesity and elevated lipids exhibited a heartmurmur, shortness of breath out of proportion to her weight and age, lowblood pressure, and leg edema. She underwent an echocardiogram, whichshowed mitral regurgitation of 1-2+ and mild elevation in pulmonaryartery pressure of 36 mm Hg. She was 66″ tall, weight 282 lbs, BMI 46,initial BP 118/80. She had 2+ edema of both ankles, clear lungs, and asystolic murmur along the left sternal border, grade II/VI.

She was started on atorvastatin 10 mg daily as well as bupropion 150 mgdaily and topiramate 200 mg daily along with a low fat, low carbohydratediet and exercise. Two weeks after the start of her weight loss programshe reported that her exercise tolerance was markedly improved andprevious chest pressure and shortness of breath on exertion were gone.She lost weight continuously on the program and 4 months later had lost20 lbs. A repeat echocardiogram taken 2 weeks after the start oftreatment showed only 1+ mitral regurgitation and normal pulmonarypressures. After six months, the patient temporarily discontinued themedications. Within a few days, even though her weight was the same, herchest pressure and shortness of breath on exertion returned. Onresumption of the treatment, the symptoms resolved within a few days.

EXAMPLE 2

The second patient was a 57 year-old female with obesity,hypothyroidism, hypertension, valvular heart disease, elevatedcholesterol and depression. Her medications were levothyroxine 50 mcgdaily, metoprolol 50 mg daily, venlafaxine 37.5 mg daily, progesterone100 mg daily, esterified estrogens 1.25 mg daily, and methyltestosterone2.5 mg daily. She was 63″ tall, weight 178 lbs, BMI 32, initial BP120/78. She had trace edema of both ankles and a systolic murmur of I/VIalong the left sternal border. An echocardiogram obtained nine monthsbefore obesity treatment because of her heart murmur and edema showedmild MR, moderate TR and pulmonary hypertension with a pressure of 39 mmHg noted. A comment on the report stated that this was a slight increasein pulmonary pressure compared with an echocardiogram taken seven monthsearlier.

She was treated with phentermine 15 mg daily and topiramate 200 mg dailyalong with a low fat, low carbohydrate diet and exercise. Metoprolol wasdiscontinued after four months due to low blood pressure. Eight monthsafter treatment started, her weight was 165 lbs, BP was 122/76, and shehad no edema. A repeat echocardiogram 1 month later (nine months ontreatment for obesity) showed that the pulmonary artery pressure was 33mm Hg and the tricuspid regurgitation was now rated as mild. No MR wasseen.

EXAMPLE 3

The third patient was a 62 year-old female with obesity, hypertension,elevated cholesterol, heart murmur and dyspnea on exertion. Hermedications were atorvastatin 10 mg daily, captopril 12.5 mg daily,trazodone 50 mg daily, spironolactone 50 mg daily, and bupropion 150 mgdaily. She was 64″ tall, weight 319 lbs, BMI 55, initial BP 148/76. Shehad a systolic murmur of I/VI loudest along the left sternal border. Anechocardiogram showed mild tricuspid regurgitation, normal LV size andfunction with probable mild pulmonary hypertension.

She was treated with phentermine 15 mg daily and topiramate 200 mg dailyalong with a low fat, low carbohydrate diet and exercise. She wasinstructed to stop both the spironolactone and captopril since thisweight loss treatment results in marked lowering of blood pressure inmost patients. Three weeks later, before significant weight loss hadoccurred, a repeat echocardiogram showed no findings of pulmonaryhypertension. Blood pressure one week later was 140/86 and weight 317lbs.

EXAMPLE 4

The fourth patient was a 56 year-old female with obesity, sleep apnea onCPAP, known pulmonary hypertension with PA pressure estimated at 76 mmHg by echocardiogram, valvular heart disease (mild-moderate tricuspidand mitral regurgitation), depression and hypertension. She smoked justunder half pack of cigarettes per day and was a CO2 retainer by ABG'swith a PCO2 of 54 mm Hg on room air. She was short of breath withminimal exertion. Her baseline medications were furosemide 80 mg daily,potassium chloride 20 mEq daily, lisinopril 10 mg daily, carvedilol 25mg BID, escitalopram 10 mg daily, alprazolam 0.5 mg TID, and nightlyoxygen. She was 68″ tall, weight 284 lbs, BMI 43½, initial BP 122/76.She had 1+ edema of both lower legs and was short of breath on exertion.

She was treated with aspirin 81 mg coated daily, bupropion 300 mg daily,topiramate 100 mg daily, phentermine 5 mg daily, along with a low fat,low carbohydrate diet and light exercise. By the first 4 weeks offollow-up, she had lost 17 lbs and was breathing much better. Fourmonths into the treatment she was clinically markedly improved and ableto exercise normally without shortness of breath. She was still smokingcigarettes occasionally. She had lost 38 lbs. Her blood pressure was110/70 on only lisinopril 10 mg daily. Furosemide and carvedilol hadbeen gradually discontinued due to improved edema, blood pressure, andbreathing. An echocardiogram performed at three months into the programwas mostly unchanged from her prior echocardiogram except that thepulmonary artery pressure was reported as normal. This change wasconsistent with her clinical picture.

EXAMPLE 5

The fifth patient was a 70 year-old female with obesity, diabetes,hypertension, hypothyroidism, elevated cholesterol, COPD, and pulmonaryhypertension. An echocardiogram 2 years previously showed mild LVH,mild-moderate tricuspid regurgitation, mild RVH, and elevated pulmonaryartery pressure of 45-50 mm Hg. She had stopped smoking 1PPD about 10years previously. Her baseline medications were verapamil 240 mg daily,losartan-HCTZ 50-12.5 daily, levothyroxine 0.125 mg daily, Pulmicort 200mg 2 puffs twice daily, Foradil powder 12 mg twice daily, metformin 500mg twice daily, atorvastatin 10 mg daily, fluticasone nasal spray 50 mcg2 puffs daily and vitamins. She was short of breath with minimalexertion. She was 67″ tall, weight 228 lbs, BMI 36, initial BP 138/70.

She was treated with phentermine 15 mg daily and topiramate 100 mgdaily. Three years into treatment, her fasting glucose is 106 offmetformin compared with 114 on metformin at baseline, her blood pressureis 115/60 on valsartan 80 mg daily and diltiazem CD 120 mg daily(changed from verapamil because of constipation). Her weight has beenstable for six months in the low 180's. A follow-up echocardiogram 30months into treatment showed normal pulmonary pressures. She was alsosymptomatically much better and exercising more without shortness ofbreath.

These five patients showed a surprising improvement in pulmonaryhypertension, with marked improvement in symptoms in two patients evenbefore significant time had elapsed, and symptomatic improvement in allpatients. In addition to treatment with topiramate, a carbonic anhydraseinhibitor, these patients were also subject to a low fat, lowcarbohydrate diet and weight loss program that typically resulted inmild diuresis and lower blood pressures. However, the improvement inpulmonary pressures appeared to be independent of weight loss in thesepatients.

EXAMPLE 6

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 25 mgzonisamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLE 7

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 50 mgzonisamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLE 8

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 100 mgzonisamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLE 9

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 100 mgacetazolamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLE 10

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 250 mgacetazolamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLE 11

The procedure of Example 1 is repeated with a patient exhibiting similarsymptoms with respect to pulmonary hypertension, except that 500 mgacetazolamide is substituted for the topiramate. Substantially the sameresults are expected.

EXAMPLES 12-17

The procedures of Examples 2 through 5 are repeated with patientsexhibiting similar symptoms with respect to pulmonary hypertension,except that the following are substituted for the amount of topiramategiven: 25 mg, 50 mg, and 100 mg zonisamide; and 100 mg, 250 mg, and 500mg acetazolamide. Substantially the same results are expected.

EXAMPLE 18

Sustained release dosages in the form of gelatin capsules were preparedwith a target dose of 15 mg phentermine and 100 mg topiramate percapsule. Phentermine beads were prepared using 20/25 mesh sugar spheresNF and a drug layering solution containing components selected fromphentermine, METHOCEL® E5 (hypromellose, produced by The Dow ChemicalCompany), and water. Topiramate beads were prepared using a spheronizedcore, a CR coating, and an enteric coating. The spheronized corecontained components selected from topiramate, AVICEL® PH102(microcrystalline cellulose, supplied by FMC BioPolymer), and METHOCEL®A15LV (methylcellulose, produced by The Dow Chemical Company). The CRcoating solution contained components selected from EUDRAGIT® RSPO (lesspermeable, amino methacrylate copolymer, supplied by Degussa PharmaPolymers, Germany), EUDRAGIT® RLPO (more permeable, amino methacrylatecopolymer, supplied by Degussa Pharma Polymers, Germany), glycerolmonostearate, isopropyl alcohol, and acetone. The enteric coatingsolution contained components selected from EUDRAGIT® S100 (copolymer ofmethacrylic acid and methyl methacrylate, supplied by Degussa PharmaPolymers, Germany), glycerol monostearate, isopropyl alcohol, andacetone. Weight percentages (theoretical—not measured) for the finalcompositions are summarized in Tables 1-3.

TABLE 1 Formulation Summary - capsules containing phentermine beads andtopiramate beads Final composition, Final composition, phenterminebeads¹ topiramate beads² Percent Percent Material w/w Material w/wPhentermine 7.63 Topiramate 31.89 METHOCEL ® E5 7.63 AVICEL ® PH10245.04 20/25 Sugar Sphere, NF 84.75 METHOCEL ® A15LV 2.79 Total 100.00EUDRAGIT ® RSPO 0.00 EUDRAGIT ® RLPO 9.28 Glycerol Monostearate 0.29EUDRAGIT ® S100 10.39 Glycerol Monostearate 0.32 Total 100.00 ¹Targetfill weight = 230.7 mg; ²Target fill weight = 313.6 mg.

TABLE 2 Formulation Summary - capsules containing phentermine beads andtopiramate beads Final composition, Final composition, phenterminebeads¹ topiramate beads² Percent Percent Material w/w Material w/wPhentermine 7.63 Topiramate 31.89 METHOCEL ® E5 7.63 AVICEL ® PH10245.04 20/25 Sugar Sphere, NF 84.75 METHOCEL ® A15LV 2.79 Total 100.00EUDRAGIT ® RSPO 4.64 EUDRAGIT ® RLPO 4.64 Glycerol Monostearate 0.29EUDRAGIT ® S100 10.39 Glycerol Monostearate 0.32 Total 100.00 ¹Targetfill weight = 230.7 mg; ²Target fill weight = 313.6 mg.

TABLE 3 Formulation Summary - capsules containing phentermine beads andtopiramate beads Final composition, Final composition, phenterminebeads¹ topiramate beads² Percent Percent Material w/w Material w/wPhentermine 7.63 Topiramate 31.89 METHOCEL ® E5 7.63 AVICEL ® PH10245.04 20/25 Sugar Sphere, NF 84.75 METHOCEL ® A15LV 2.79 Total 100.00EUDRAGIT ® RSPO 6.50 EUDRAGIT ® RLPO 2.78 Glycerol Monostearate 0.29EUDRAGIT ® S100 10.39 Glycerol Monostearate 0.32 Total 100.00 ¹Targetfill weight = 230.7 mg; ²Target fill weight = 313.6 mg.

EXAMPLE 19

Dosages in the form of gelatin capsules were prepared with a target doseof 100 mg topiramate per capsule. Topiramate beads were prepared using aspheronized core, an optional CR coating, and an optional entericcoating. The spheronized core contained components selected fromtopiramate, AVICEL® PH102, and METHOCEL®A15LV. The CR coating solutioncontained components selected from ethylcellulose (Ethocel PremiumStandard 10), Povidone K-30, ethanol (absolute SD3 A), EUDRAGIT® RLPO(more permeable), glycerol monostearate, isopropyl alcohol, and acetone.The enteric coating solution contained components selected fromEUDRAGIT® 100, EUDRAGIT® L100-55, glycerol monostearate, isopropylalcohol, and acetone. Weight percentages (theoretical—not measured) forthe final compositions are summarized in Tables 4-8. Table 4 describescapsules containing spheronized topiramate beads without a CR coatingand without an enteric coating. Tables 5 and 6 describe capsulescontaining spheronized topiramate beads with a CR coating but without anenteric coating. Tables 7 and 8 describe capsules containing spheronizedtopiramate beads with an enteric coating but without a CR coating.

TABLE 4 Formulation Summary - capsules containing spheronized topiramatebeads Final composition, topiramate beads¹ Material Percent w/wTopiramate 40.00 AVICEL ® PH102 56.50 METHOCEL ® A15LV 3.50 Total 100.00¹Target fill weight = 250.0 mg.

TABLE 5 Formulation Summary - capsules containing spheronized topiramatebeads and a CR coating Final composition, topiramate beads¹ MaterialPercent w/w Topiramate 36.36 AVICEL ® PH102 51.36 METHOCEL ® A15LV 3.18Ethylcellulose 6.36 Povidone K-30 2.73 Total 100.00 ¹Target fill weight= 275.0 mg.

TABLE 6 Formulation Summary - capsules containing spheronized topiramatebeads and a CR coating Final composition, topiramate beads¹ MaterialPercent w/w Topiramate 35.71 AVICEL ® PH102 50.45 METHOCEL ® A15LV 3.13EUDRAGIT ® RLPO 10.39 Glycerol Monostearate 0.32 Total 100.00 ¹Targetfill weight = 280.0 mg.

TABLE 7 Formulation Summary - capsules containing spheronized topiramatebeads and an enteric coating Final composition, topiramate beads¹Material Percent w/w Topiramate 35.71 AVICEL ® PH102 50.45 METHOCEL ®A15LV 3.13 EUDRAGIT ® S100 10.39 Glycerol Monostearate 0.32 Total 100.00¹Target fill weight = 280.0 mg.

TABLE 8 Formulation Summary - capsules containing spheronized topiramatebeads and an enteric coating Final composition, topiramate beads¹Material Percent w/w Topiramate 35.71 AVICEL ® PH102 50.45 METHOCEL ®A15LV 3.13 EUDRAGIT ® L100-55 10.39 Glycerol Monostearate 0.32 Total100.00 ¹Target fill weight = 280.0 mg.

EXAMPLE 20

Dosages in the form of gelatin capsules were prepared with a target doseof 100 mg topiramate per capsule. Spheronized topiramate beads wereprepared using components selected from topiramate, METHOCEL® A15LV,ACDISOL®, AVICEL® PH102, and lactose monohydrate. Weight percentages(theoretical—not measured) for the final compositions are summarized inTables 9-10. In addition to the dosage forms described in Tables 9-10, acapsule was prepared continuing 100 wt % topiramate (target fillweight=100.0 mg).

TABLE 9 Formulation Summary - capsules containing spheronized topiramatebeads Final composition, topiramate beads¹ Material Percent w/wTopiramate 40.00 AVICEL ® PH102 41.00 METHOCEL ® A15LV 9.00 ACDISOL ®10.00 Total 100.00 ¹Target fill weight = 250.0 mg.

TABLE 10 Formulation Summary - capsules containing spheronizedtopiramate beads Final composition, topiramate beads¹ Material Percentw/w Topiramate 40.00 AVICEL ® PH102 36.00 METHOCEL ® A15LV 4.00 Lactosemonohydrate 20.00 Total 100.00 ¹Target fill weight = 250.0 mg.

1. A method for treating primary pulmonary hypertension in a patient,comprising administering a therapeutically effective dose of topiramateand a therapeutically effective dose of a Type V phosphodiesteraseinhibitor to the patient.
 2. The method of claim 1, wherein the type Vphosphodiesterase inhibitor treats an adverse physiological condition inaddition to primary pulmonary hypertension.
 3. The method of claim 2,wherein the physiological condition is congestive heart failure.
 4. Themethod of claim 1, wherein the type V phosphodiesterase inhibitoradditionally improves the patient's cardiac index.
 5. The method ofclaim 1, wherein the topiramate is contained in a pharmaceuticalformulation that further comprises at least one pharmaceuticallyacceptable excipient.
 6. The method of claim 5, wherein thepharmaceutical formulation is a controlled release dosage form.
 7. Themethod of claim 6, wherein the controlled release dosage form providesfor sustained release of the topiramate following administration of thedosage form to the patient.
 8. The method of claim 7, wherein theformulation provides for a substantially constant plasma level of thetopiramate over a time period in the range of about 4 to 12 hours. 9.The method of claim 1, wherein the topiramate is administered to thepatient in an amount in the range of about 10 mg to about 400 mg perday.
 10. The method of claim 9, wherein the topiramate is administeredto the patient in an amount in the range of about 50 mg to about 250 mgper day.
 11. The method of claim 10, wherein the topiramate isadministered to the patient in an amount in the range of about 75 mg toabout 225 mg per day.
 12. The method of claim 1, wherein the Type Vphosphodiesterase inhibitor is selected from avanafil, sildenafil,tadalafil, zaprinast, dipyridamole, vardenafil and acid addition saltsthereof.
 13. The method of claim 12, wherein the Type Vphosphodiesterase inhibitor is avanafil.
 14. The method of claim 13,wherein the weight ratio of topiramate administered to the avanafiladministered is in the range of about 3:1 to about 1:3.
 15. The methodof claim 14, wherein the weight ratio of topiramate administered to theavanafil administered is in the range of about 2:1 to about 1:2.
 16. Themethod of claim 1, wherein the topiramate and the Type Vphosphodiesterase inhibitor are administered at different times of theday.
 17. The method of claim 1, wherein the topiramate and the Type Vphosphodiesterase inhibitor are administered simultaneously.
 18. Themethod of claim 17, wherein the topiramate and the Type Vphosphodiesterase inhibitor are contained in a single formulation. 19.The method of claim 18, wherein the formulation comprises an orallyadministrable dosage form that, following oral administration of thedosage form to the patient, provides for controlled release of thetopiramate, and either immediate release or controlled release of theType V phosphodiesterase inhibitor.
 20. The method of claim 19, whereinthe formulation provides for controlled release of the phosphodiesteraseinhibitor.
 21. The method of claim 20, wherein the formulation providesfor sustained release of the phosphodiesterase inhibitor.
 22. A methodfor treating primary pulmonary hypertension in a patient, comprisingadministering to the patient: a daily dose of topiramate that isgradually increased, over an extended time period, from an initial dailydosage up to a final daily dosage suitable for continued maintenancetherapy, wherein the final daily dosage is in the range of about 10 mgto 400 mg, and a Type V phosphodiesterase inhibitor.
 23. The method ofclaim 22, wherein the final daily dosage is in the range of about 50 mgto about 250 mg.
 24. The method of claim 22, wherein the final dailydosage is in the range of about 75 mg to about 225 mg.
 25. The method ofclaim 22, wherein the initial daily dosage is in the range of about 10mg to about 40 mg.
 26. The method of claim 25, wherein the initial dailydosage is in the range of about 15 mg to about 35 mg.
 27. The method ofclaim 22, wherein the extended time period is in the range of aboutthree weeks to about ten weeks.
 28. The method of claim 12, wherein theType V phosphodiesterase inhibitor is tadalafil.
 29. The method of claim28, wherein the weight ratio of topiramate administered to the tadalafiladministered is in the range of about 36:1 to about 4:1.
 30. The methodof claim 29, wherein the weight ratio of topiramate administered to thetadalafil administered is in the range of about 24:1 to about 6:1.